Abstract
Renal fibrosis and anaemia are two of the most relevant events in chronic kidney disease. Fibrosis is characterized by the accumulation of extracellular matrix proteins in the glomeruli and tubular interstitium. Anaemia is the consequence of a decrease in erythropoietin production in fibrotic kidneys. This work analyses the possibility that the accumulation of abnormal collagens in kidney interstitium could be one of the mechanisms responsible for erythropoietin decreased synthesis. In renal interstitial fibroblast grown on collagen I, erythropoietin mRNA expression and HIF‐2α protein decreased, whereas focal adhesion kinase protein (FAK) phosphorylation and proteasome activity increased, compared to cells grown on collagen IV. Proteasome inhibition or FAK inactivation in cells plated on collagen I restored erythropoietin and HIF‐2α expression. FAK inhibition also decreased the collagen I‐dependent proteasome activation. In a model of tubulointerstitial fibrosis induced by unilateral ureteral obstruction in mice, increased collagen I protein content and an almost complete disappearance of erythropoietin mRNA expression were observed in the ureteral ligated kidney with respect to the contralateral control. Interestingly, erythropoietin synthesis was recovered in obstructed mice treated with proteasome inhibitor. These data suggest that reduced kidney erythropoietin synthesis could be caused by the accumulation of abnormal extracellular matrix proteins.
Highlights
Extracellular matrix (ECM) is one of the main components of the different tissues and organs
The physiological stimulus of EPO synthesis, increased EPO protein levels in TK173 cells after 24 hrs (Fig. 1E). These results indicate that erythropoietin is down-regulated in a time- and proportion-dependent manner when cells are grown on collagen type I (COLI) versus collagen type IV (COLIV)
PP2, a selective inhibitor of focal adhesion kinase protein (FAK) activation, exerted the same effects as siFAK on the COLIinduced EPO mRNA downregulation (Fig. 5E). These results show that FAK is a relevant integrin-linked protein involved in the EPO modulation induced by COLI
Summary
Extracellular matrix (ECM) is one of the main components of the different tissues and organs. It plays a critical role in maintaining the structure of tissues, but it modulates the phenotype of adjacent cells. ECM is composed by proteins such as laminin, fibronectin and collagens. ECM proteins accumulate in the tissue, and abnormal ECM components appear in organs in which they are not usually present [1]. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine
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